UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
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FORM 8-K
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CURRENT REPORT
Pursuant to Section 13 OR 15(d)
of The Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): November 29, 2022
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Item 7.01. Regulation FD Disclosure.
On November 29, 2022, Context Therapeutics Inc. issued a press release announcing the selection of CTIM-76, its lead clinical development candidate to target Claudin 6 (CLDN6) positive cancers, and that the Company would be holding a webinar on December 1, 2022 regarding CTIM-76. A copy of the press release is filed as Exhibit 99.1 to this Current Report on Form 8-K and incorporated herein by reference.
On December 1, 2022, the Company will be presenting information during the webinar regarding the identification of CTIM-76. A copy of the presentation is filed as Exhibit 99.2 to this Current Report on Form 8-K and incorporated herein by reference.
The information in this Item 7.01 and Exhibits 99.1 and 99.2 attached hereto are being furnished and shall not be deemed “filed” for the purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, regardless of any general incorporation language in such filing.
Item 8.01. Other Events.
On November 29, 2022, Context Therapeutics Inc. issued a press release announcing the selection of CTIM-76, a T cell-engaging bispecific antibody, as the Company's lead clinical development candidate to target Claudin 6 (CLDN6) positive cancers, resulting from the Company's research collaboration and licensing agreement with Integral Molecular.
Item 9.01. Exhibits.
(d) Exhibits
| Exhibit No. | Description | |||||||
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| 99.2 | ||||||||
| 104 | Cover Page Interactive Data File (embedded within the inline XBRL document) | |||||||
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Dated: December 1, 2022 | Context Therapeutics Inc. | ||||
By: /s/ Martin A. Lehr | |||||
| Name: Martin A. Lehr | |||||
| Title: Chief Executive Officer | |||||
Context Therapeutics® Nominates CTIM-76 Bispecific Antibody Candidate to Develop Treatment for Claudin 6-Positive Solid Tumors
CTIM-76 named as lead candidate to target Claudin 6 positive cancers
IND submission expected in Q1 2024
Context to host webinar on Thursday, December 1, 2022, at 11 a.m. ET
PHILADELPHIA, PA — November 29, 2022—Context Therapeutics Inc. (“Context” or the “Company”) (Nasdaq: CNTX), a women’s oncology company developing novel treatments for breast and gynecologic cancers, today announced the selection of CTIM-76, a T cell-engaging bispecific antibody, as its lead clinical development candidate to target Claudin 6 (CLDN6) positive cancers, resulting from its research collaboration and licensing agreement with Integral Molecular.
CLDN6 is differentially expressed on cancer cells with no or very low expression in normal, healthy tissue. CLDN6-enriched cancers include ovarian, endometrial, testicular, and gastric, among others. With the potential to reach a large patient population and selective expression on cancer cells, CLDN6 has emerged as an exciting drug target.
Context’s lead candidate, CTIM-76, is a CLDN6 x CD3 bispecific antibody that incorporates a highly selective CLDN6 binding arm and a CD3 binding single-chain Fv domain in an IgG format with a silenced Fc that is designed to be functionally monovalent to avoid aberrant T-cell activation and to enhance the safety profile. Research has demonstrated that CTIM-76 is potent with specific lysis of CLDN6+ cancer cells over normal cells and can activate cytotoxic T cells without concomitant activation of free cytokines – critical determinants of immunotherapy safety and activity. Preclinical studies suggest the potential for convenient dosing with low immunogenicity risk and manufacturing can be scalable to address the significant number of patients who are potentially eligible for CTIM-76 therapy.
“This year has been marked by several exciting and significant milestones for Context, culminating in naming our lead CLDN6 clinical development candidate, CTIM-76, a bispecific antibody showing high selectivity for CLDN6,” said Martin Lehr, CEO of Context Therapeutics. “We selected this bispecific based on the specificity which suggests its potential to address the need for potent therapeutic modalities for cancer without compromising patient safety. With the selection of CTIM-76 as our lead CLDN6 candidate, we are well-positioned to rapidly advance our clinical development plan in CLDN6-positive tumors including, but not limited to, ovarian cancer. We have initiated IND-enabling studies and expect to submit our Investigational New Drug Application (IND) for CTIM-76 to the U.S. Food and Drug Administration in Q1 2024.”
“Despite being an attractive target, therapeutic monoclonal antibodies (MAbs) targeting CLDN6 are difficult to discover due to an abundance of closely related family members and an absolute need for high specificity. Context and Integral Molecular have been able to isolate and optimize rare antibodies against CLDN6 that do not cross-react with other CLDN family members,” said Joseph Rucker, Ph.D., VP of R&D at Integral Molecular.
R&D Webinar
On Thursday, December 1, 2022, at 11 a.m. ET, members of the Context team, including management, and Integral Molecular will host a webinar to discuss the selection process and
nomination of CTIM-76. There will be a question-and-answer period following the formal presentation. To register for the webinar, please visit https://edisongroup.zoom.us/webinar/register/WN_Am1qwkDwRiSYJm51SpP-TQ.
About Context Therapeutics®
Context Therapeutics Inc. (Nasdaq: CNTX) is a clinical-stage biopharmaceutical company committed to advancing medicines for female cancers. The Company’s pipeline includes small molecule and bispecific antibody drug candidates that target cancer signaling pathways. Onapristone extended release (ONA-XR), a novel, first-in-class potent and selective progesterone receptor antagonist, is currently in three Phase 2 clinical trials and one Phase 1b/2 clinical trial in hormone-driven breast, ovarian, and endometrial cancers. Context is also developing CTIM-76, a selective Claudin 6 (CLDN6) x CD3 bispecific antibody for CLDN6 positive tumors, currently in preclinical development. Context is headquartered in Philadelphia. For more information, please visit www.contexttherapeutics.com or follow the Company on Twitter and LinkedIn.
Forward-looking Statements
This press release contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact, included in this press release regarding strategy, future operations, prospects, plans and objectives of management, including words such as "may," "will," "expect," "anticipate," "plan," "intend," and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are forward-looking statements. These include, without limitation, statements regarding (i) the selectivity, dosing convenience, potency, binding, scalable manufacturing, and safety profile of CTIM-76, (ii) the expectation to have an IND submission for CTIM-76 in the first quarter of 2024, (iii) the results of our IND-enabling studies and clinical trials, (iv) the potential benefits of our product candidates, (v) the likelihood data will support future development, and (vi) the likelihood of obtaining regulatory approval of our product candidates. Forward-looking statements in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Other factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in our filings with the U.S. Securities and Exchange Commission, including the section titled “Risk Factors” contained therein. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise.
This press release contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact, included in this press release regarding strategy, future operations, prospects, plans and objectives of management, including words such as "may," "will," "expect," "anticipate," "plan," "intend," and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are forward-looking statements. These include, without limitation, statements regarding (i) the selectivity, dosing convenience, potency, binding, scalable manufacturing, and safety profile of CTIM-76, (ii) the expectation to have an IND submission for CTIM-76 in the first quarter of 2024, (iii) the results of our IND-enabling studies and clinical trials, (iv) the potential benefits of our product candidates, (v) the likelihood data will support future development, and (vi) the likelihood of obtaining regulatory approval of our product candidates. Forward-looking statements in this release involve substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward-looking statements, and we, therefore cannot assure you that our plans, intentions, expectations or strategies will be attained or achieved. Other factors that may cause actual results to differ from those expressed or implied in the forward-looking statements in this press release are discussed in our filings with the U.S. Securities and Exchange Commission, including the section titled “Risk Factors” contained therein. Except as otherwise required by law, we disclaim any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise.
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Laine Yonker
Edison Group
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December 1, 2022 Identification of CTIM-76, a CLDN6 x CD3 bispecific antibody
Important Notice and Disclaimers Except for statements of historical fact, any information contained in this presentation may be a forward-looking statement that reflects the Company’s current views about future events and are subject to risks, uncertainties, assumptions and changes in circumstances that may cause events or the Company’s actual activities or results to differ significantly from those expressed in any forward-looking statement. In some cases, you can identify forward- looking statements by terminology such as “may”, “will”, “should”, “plan”, “predict”, “expect,” “estimate,” “anticipate,” “intend,” “goal,” “strategy,” “believe,” “could”, “would”, “potential”, “project”, “continue” and similar expressions and variations thereof. Forward-looking statements may include statements regarding the Company’s business strategy, cash flows and funding status, potential growth opportunities, clinical development activities, the timing and results of preclinical research, clinical trials and potential regulatory approval and commercialization of product candidates. Although the Company believes that the expectations reflected in such forward- looking statements are reasonable, the Company cannot guarantee future events, results, actions, levels of activity, performance or achievements. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those described under the heading “Risk Factors” in documents the Company has filed with the SEC. These forward-looking statements speak only as of the date of this presentation and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. 2 Certain information contained in this Presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and the Company's own internal estimates and research. While the Company believes these third-party sources to be reliable as of the date of this Presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this Presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. This presentation discusses product candidates that are under clinical study and which have not yet been approved for marketing by the U.S. Food and Drug Administration. No representation is made as to the safety or effectiveness of these product candidates for the use for which such product candidates are being studied. While the Company believes its internal research is reliable, such research has not been verified by any independent source. All the scientific and clinical data presented within this presentation are – by definition prior to completion of the clinical trial and a clinical study report – preliminary in nature and subject to further quality checks including customary source data verification. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. Forward Looking Statement CLDN6 Candidate Selection
Overview Martin Lehr – Chief Executive Officer Claudin 6 Target Biology Eric Butz, PhD – Scientific Lead Discovery of CTIM-76 Joseph Rucker, PhD – Research Lead Concluding Remarks Martin Lehr – Chief Executive Officer Q&A Session
Overview Martin Lehr – Chief Executive Officer
Context Therapeutics Overview CLDN6 Candidate Selection5 Company Overview Focus on Women’s Oncology • Unmet clinical need in breast, ovarian, and endometrial cancers ONA-XR oral PR antagonist • ONA-XR is a novel, potentially first-in-class progesterone receptor (PR) antagonist • Endometrial cancer Phase 2 trial initial data reports 4-month PFS rate of 77%1 • Breast cancer SMILE trial initial data to be presented Dec. 7 at San Antonio Breast Cancer Symposium • Breast cancer ELONA trial Phase 1b data expected Q4 2023 CTIM-76 CLDN6 x CD3 bispecific antibody • Claudin 6 (CLDN6) is uniquely expressed in certain adult and pediatric cancers • CTIM-76 is Context’s CLDN6 x CD3 bispecific antibody Development Candidate • IND submission on track for Q1 2024 Cash Guidance • Expected cash runway into Q1 2024 1 Data cut off as of September 30, 2022; preliminary raw data
Pipeline 6 1 Tyligand Biosciences Ltd licensed rights to ONA-XR in China, HK, Macau * Investigator Sponsored Trial Cancer Clinical Indication Preclinical Phase 1 Clinical Phase 2 Clinical Milestones ONA-XR (PR antagonist)1 Breast Cancer 2L/3L ER+,PR+,HER2- Combination w/ elacestrant Initiated Q4 2022 Phase 1b data Q4 2023 2L/3L ER+,PR+,HER2- Combination w/ fulvestrant Initial data Dec 2022 Endometrial Cancer Recurrent PR+ Endometrioid Combination w/ anastrozole Initial data Q4 2022 Data update mid-2023 Ovarian Cancer Recurrent PR+ Granulosa Cell Tumor Combination w/ anastrozole Initial data Q4 2022 Data update mid-2023 CTIM-76 (CLDN6xCD3 bispecific antibody) CLDN6-positive cancers Candidate selection Q4 2022 IND submission Q1 2024 Phase 1b/2 ELONA Trial *Phase 2 SMILE Trial *Phase 2 Trial *Phase 2 Trial Company Overview CLDN6 Candidate Selection
Claudin 6 Target Biology Eric Butz, PhD – Scientific Lead
Claudin 6 (CLDN6) is an Emerging Oncology Target Opportunity • CLDN6 is a tumor-specific protein that is present at high surface density across certain adult and pediatric cancers1 • CLDN6 is expressed at very low levels or absent in normal adult tissue Challenge • CLDN6 antigen is conformationally dependent, which limits access to antibody-antigen binding • Antigen binding region is highly conserved with CLDN3, CLDN4, and CLDN9 • CLDN6 selectivity is required to avoid off-target liabilities identified in murine knockout studies with CLDN3 (pancreas), CLDN4 (kidney, pancreas), and CLDN9 (ear, gut) Target Validation • BNT211 CAR-T establishes Proof of Concept2: ‒ Novel CAR-T + mRNA vaccine evaluated in Phase 1 dose-escalation study in CLDN6+ solid tumors ‒ 50% response rate (ORR) in second dosing cohort Unmet Need • Selectivity: preferentially target CLDN6 over other CLDN proteins • Potency: specific lysis of CLDN6+ cancer cells over normal cells • Safety: activation of cytotoxic T cells without concomitant activation of free cytokines • Manufacturability: scalable process and on-demand therapy CLDN6 Target Biology CLDN6 Candidate Selection8 1 Faber MS, et al. Bispecific claudin-6 x CD3 antibodies AACR Annual Meeting; 2021; Virtual. Abstract 1860 2 Haanen JB, et al. BNT211: A Phase I trial. ESMO Annual Meeting; 2022; Paris, France. LBA38
Claudin (CLDN) Protein Family • Tight junctions (TJ) regulate cell barrier and permeability • CLDN proteins constitute a structural core of TJ, along with junction adhesion molecule (JAM) and occludin • 27 CLDN proteins have been characterized to date • Dysregulation of CLDN protein expression and function occurs in multiple diseases, including cancer CLDN6 Target Biology CLDN6 Candidate Selection9 Otani, Trends in Cell Biology, 2020 Tight Junction Structure
Many CLDN Proteins are Associated with Disease CLDN6 Target Biology CLDN6 Candidate Selection10 CLDN Disease CLDN 1 Colitis, skin permeability CLDN 2 Colorectal cancer, IBD CLDN 3 Psoriasis, ovarian cancer CLDN 4 Diabetes, ovarian cancer CLDN 5 Cerebral edema, depression CLDN 6 Multiple cancers CLDN 7 Colon cancer CLDN 9 Hearing loss CLDN Disease CLDN 11 Myelin dysfunction CLDN 14 Kidney stones, hearing loss CLDN 15 Celiac CLDN 16 Hypercalcinuria CLDN 17 Renal dysfunction CLDN 18.2 Gastric cancer CLDN 19 Renal dysfunction, vision loss
The Challenge: developing a highly selective CLDN6 antibody CLDN6 Target Biology CLDN6 Candidate Selection11 CLDN9 CLDN6 CLDN4 CLDN3 CLDN5 CLDN8 CLDN17 CLDN2 CLDN14 CLDN20 CLDN7 CLDN1 CLDN19 CLDN34 CLDN12 CLDN23 CLDN16 CLDN24 CLDN22 CLDN25 CLDN18 CLDN11 CLDN15 CLDN10 • CLDN6 antigen is conformationally-dependent, which limits access to antibody-antigen binding • Antigen binding region is highly conserved with CLDN3, CLDN4, and CLDN9, making target selectivity a challenge1 • CLDN6 selectivity is required to avoid off-target liabilities identified in murine knockout studies with CLDN3 (pancreas)2, CLDN4 (kidney, pancreas)3, and CLDN9 (ear)4 3 Cordat, Physiology, 2019; Li, FEBS Open Bio, 2020 4 Nakano, PLoS Genet, 2009; 1 Screnci, Cancer Res, 2022 2 Tanaka, J Hepatol, 2018 Human CLDN Family Tree
CLDN6 is an Oncofetal Protein, Considered Favorable Candidates for Immunotherapy CLDN6 Target Biology CLDN6 Candidate Selection12 • Normally present at higher levels during embryonic development • Turned off or have low levels of expression in adult tissues • Increased expression of these antigens can occur in some tumor cells, and are referred to as “tumor-associated antigens” or TAA CLDN6 Biology
CLDN6 is Selectively Expressed on Cancer Cells CLDN6 Target Biology CLDN6 Candidate Selection13 (a) adrenal gland, (b) fallopian tube, (c) kidney, (d) liver, (e) thyroid, (f) prostate, (g) esophagus, (h) stomach, (i) colon, (j) cerebrum, (k) cerebellum, (l) spinal cord. (m) thymus, (n) spleen, (o) bone marrow, (p) pancreas, (q) skin, (r) bladder, (s) placenta, (t) heart muscle, (u) striated muscle, (v) testis, (w) ovary, (x) lung (CA1) testicular cancer, (CA2) ovarian cancer, and (CA3) lung cancer Reinhard, Science, 2020 Normal Tissue Cancer Tissue
CLDN6 Exhibits High, Homogeneous Expression on Cancer Cells • CLDN6 protein expression in testicular and ovarian tumors each from eight different patients analyzed by IHC • Testicular: all embryonal carcinoma • Ovarian: (a) adenocarcinoma, (b,c,e-h) serous cystadenocarcinoma, (d) papillary serous cystadenocarcinoma CLDN6 Target Biology CLDN6 Candidate Selection14 Reinhard, Science, 2020 Consistent expression makes CLDN6 a promising tumor associated antigen (TAA) for immunotherapy Testicular Cancer Ovarian Cancer
CLDN6 Has the Potential to Reach a Large Patient Population ~62,500 patients per year in the US only in Relapse/Refractory Setting CLDN6 Target Biology 15 Selected Cancer indications Incidence R/R Incidence CLDN6 Positive Patient Population Based on R/R Incidence Testicular 9,910 400 95%1 380 Ovarian 19,900 12,800 54-55%1,2 6,982 NSCLC 201,229 110,653 6-50%3,4,5 35,221 Malignant Rhabdoid 50 500 29-44%1,2,6,7 183 Gastric 26,380 11,090 13-55%8,9 3,771 Breast 290,600 43,800 2-41%1,10,11 9,417 Endometrial 65,900 12,500 20-31%1,12,13 3,188 Glioma 19,000 10,000 21%8 2,100 Bladder 81,180 17,100 2-8%1,13 855 SCLC 35,511 19,527 2%1 391 1 Reinhard, Science, 2020; 2 Wang, Diagn Pathol., 2013; 3 Gao, Oncol Lett., 2013; 4 Kohmoto, Gastric Cancer, 2020; 5 Lin, Diagn Pathol., 2013; 6 Micke, Intl J Cancer, 2014; 7 Soini, Pol J Path, 2022; 8 Antonelli, Brain Pathol., 2011; 9 Sullivan, Am J Surg Pathol., 2012; 10 Jia, Intl J Clin Exp Pathol., 2019; 11 Yafang, J Breast Cancer, 2011; 12 Kojima, Cancers, 2020; 13 Ushiku, Histopath., 2012 Incidences based on public estimates; Relapsed/refractory (R/R) or last-line patient population approximated by annual mortality; CLDN6 target prevalence is based on IHC or RNAseq from published reports. Patient population derived from midpoint of CLDN6 positive population multiplied by R/R incident population. Initial indications of interest based on: • CLDN6 prevalence • Patient population size • Observed clinical responses • Eligibility for Orphan or Rare Pediatric Designation CLDN6 Candidate Selection
Key Developments in CLDN6 R&D Timeline R&D activity has recently accelerated CLDN6 Target Biology CLDN6 Candidate Selection16 1 https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002755-15/results 2 Hamilton et al, AACR, Virtual: 2020 April 2022 BNT211 (BioNTech) Clinical Proof of Concept for CLDN6 CAR-T Amgen and i-Mab announce programs at AACR 2016 Astellas acquires Ganymed and gains access to mAbs targeting CLDN6 (IMAB027) and CLDN18.2 (IMAB362) 2009 Chugai publishes patent covering anti-Claudin 6 antibodies 2019 IMAB027 (CLDN6 mAb) does not advance past Ph 2 due to a lack of activity1 2020 SC-004 ADC (Abbvie) exhibits poor tolerability in Ph 12 2021 Xencor and NovaRock announce programs at AACR
CLDN6 – Drug Development Strategy Comparison CLDN6 is a tumor-associated antigen (TAA) for tumor-targeting therapeutics such as CAR-T and T cell engaging bispecific antibodies CLDN6 Target Biology CLDN6 Candidate Selection17 Drug Development Strategy CLDN6 Dependence / Rationale Supporting Evidence Monoclonal Antibody (mAb) Receptor-mediated signaling Poor Weak signaling dependence1 Bispecific Antibody (bsAb) Cell surface antigen for T-cell targeting High In vivo PoC + BNT211 clinical PoC2,3 Antibody-Drug Conjugate (ADC) Receptor internalization Poor Weak internalization4 CAR-T Cell surface antigen for T-cell targeting High BNT211 clinical PoC3 1 https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002755-15/results . 2 Context internal 3 Haanen J, et al. AACR Annual Meeting 2022; Oral presentation CT002. 4 Data courtesy of Integral Molecular and Dr. Andrew Tsourkas (UPenn)
CLDN6 is Not Ideally Suited for Conventional mAb or ADC Therapy CLDN6 has weak signaling activity and poor internalization • CLDN6 and CLDN18.2 antibodies from Integral Molecular were converted to ADC utilizing MMAE payload • ADC constructs evaluated in OVCAR3 cell killing assay • CLDN6 ADC cell killing achieved only at supratherapeutic doses CLDN6 Target Biology CLDN6 Candidate Selection18 1 https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002755-15/results 2 Data courtesy of Integral Molecular and Dr. Andrew Tsourkas (UPenn) IMAB027 Treatment Stage 1/2 1-1000 mg/m 2 Stage 2 100 mg/m 2 Stage 2 300 mg/m 2 Stage 2 600 mg/m 2 Stage 2 1000 mg/m 2 Patients (n) 2 10 10 10 9 CR (n) 0 0 0 0 0 PR (n) 0 0 1 0 0 SD (n) 0 1 3 3 7 • 41 patients with recurrent ovarian cancer were treated with IMAB027 in a Phase 1 dose escalation trial • 1 PR and 14 SD noted • IMAB027 was well tolerated IMAB027 Phase 1 Dose Escalation Trial CLDN6 mAb Exhibits Weak Monotherapy Activity1 CLDN6 Does Not Rapidly Internalize2 OVCAR3 Cell Killing Assay
CLDN6 is an Ideal Tumor Associated Antigen for T-cell Targeting BNT211 (BioNTech) demonstrates preliminary clinical proof of concept CLDN6 Target Biology CLDN6 Candidate Selection19 • CARVac intended to drive in vivo expansion, persistence, and efficacy of CAR-T • Strategy intended to minimize number of CAR-T cells infused and offset cytokine storm risk Reinhard, Science 2020 BNT211 CAR-T + CLDN6 CARVac CARVac mRNA Vaccine Strategy
BNT211 ± CARVac Exhibited Activity Across CLDN6+ Advanced Cancers Initial clinical efficacy benchmarked to standard of care or emerging treatments CLDN6 Target Biology CLDN6 Candidate Selection20 Testicular: Haanen 2022, Oechsle 2011, Adra 2018, Necchi 2016 Ovarian: Haanen 2022, Matulonis 2022, Pujade-Lauraine 2014, Vaishampayan 2022 31% 13% 11% 0% 0% 5% 10% 15% 20% 25% 30% 35% BNT211 ± CARVac n=13 Sunitinib n=33 Brentuximab Vedotin n=9 Pembrolizumab n=12 O v e ra ll R e s p o n s e R a te ( O R R ) 50% 32% 28% 27% 0% 10% 20% 30% 40% 50% 60% BNT211 ± CARVac n=4 Mirvetuximab Soravtansine n=106 Pembrolizumab + Nemvaleukin alpha n=14 Chemotherapy + Bevacizumab n=179 O v e ra ll R e s p o n s e R a te ( O R R ) • DL1 + DL2: 13 testicular cancer patients received BNT211 ± CARVac across DL1 (1x107 cells) and DL2 (1x108 cells) for a response rate of 31% • DL2 only: Seven (7) testicular cancer patients received the second BNT211 dose level (DL2) after lymphodepletion with four (4) patients responding, including one complete response (CR), for a response rate of 57% • DL1 + DL2: 4 ovarian cancer patients received BNT211 ± CARVac for a response rate of 50% • DL2 only: Two (2) ovarian cancer patients received the second BNT211 dose level (DL2) after lymphodepletion with both patients responding for a response rate of 100% Testicular Cancer Ovarian Cancer D L 1 + D L 2 D L 1 + D L 2
Limitations of CLDN6 CAR-T + CARVac Approach CLDN6 Target Biology CLDN6 Candidate Selection21 Target Asset Ph 1 Dose Range RP2D CLDN6 BNT211 1x10 7 to 1x10 9 cells TBD CLDN18.2 CT041 2.5x10 8 to 5x10 8 cells 2.5 x 10 8 cells • BNT211 + CARVac T-cell infusion is consistent with similar CAR-T products • Without CAR-T dose sparing, patients may be exposed to high dose CAR-T side effects, including neurologic and hepatic • CAR-T activity in solid tumors is often limited by a weak durability of response • BNT211 + CARVac exhibits a limited durability of response in advanced solid tumors • CARVac is intended to enhance T-cell persistence • Preliminary findings indicate that CARVac provides limited enhancement of T-cell persistence 1 Haanen J, et al. AACR Annual Meeting 2022; Oral presentation CT002. 2 Qi C, et a. ESMO Annual Meeting 2021; Oral Presentation Virtual. RP2D = recommended Phase 2 dose Limited Dose Sparing1,2 Limited Durability1 Limited T Cell Persistence1 DL2 (1x108 CLDN6 CAR-T)
BNT211 + CARVac CTIM-76 Complex + In-Patient Hospital administered autologous cell therapy in combination with repeat mRNA vaccination utilizing lipid nanoparticle carrier Easy + Out-Patient Outpatient infusion every 2-4 weeks based on IgG backbone Required None Weak T cell persistence Fully stimulated T cell Elevated transaminase and lipase Selective for CLDN6 CTIM-76 Differentiation1 CLDN6 Target Biology CLDN6 Candidate Selection22 Administration Lymphodepletion Treatment Durability Selectivity and Safety 1 Analysis based upon publicly available information and represents a non-head-to-head summary conceptual comparison
Discovery of CTIM-76 Joseph Rucker, PhD – Research Lead
• Multiple formats evaluated Bispecific Antibody Considerations Candidates evaluated based on a range of scaffolds, CLDN6, and T-cell engagers Discovery of CTIM-76 CLDN6 Candidate Selection24 NHP = non-human primate • High affinity anti-CLDN6 binding • High specificity for CLDN6 vs other CLDN − Especially CLDN3, CLDN4, CLDN9 CLDN6 Targeting Arm • Clinically validated • Freedom to operate • Explore a range of potencies CD3 Targeting Arm Bispecific Scaffolds • Cross reactivity to NHP desirable for both arms • FcRn binding for half-life extension • Silencing variants to eliminate FcR binding Other Factors
CTIM-76 Nominated as Development Candidate Wide therapeutic window • Highly selective CLDN6 binding Fab arm • CD3 binding single-chain Fv domain is designed to be functionally monovalent to avoid aberrant T-cell activation, potentially enhancing safety profile • Silenced Fc domain to avoid T-cell activation by Fc-gamma receptor positive cells Convenient dosing with low immunogenicity risk • T-cell dependent cellular cytotoxicity with no or minimal activation of circulating cytokines • Humanized CLDN6 and CD3 binding domains Ease of manufacturing • IgG backbone is highly stable and enables high yield Discovery of CTIM-76 CLDN6 Candidate Selection25 α-CLDN6 Fab α-CD3 svFv IgG backbone
Identification of CLDN6-targeting Arm The Problem • The extracellular binding region of CLDN6 is highly conserved with CLDN3 (78% homology), CLDN4 (81%), and CLDN9 (96%) • Antigen is conformationally dependent, which limits conventional antibody discovery methods • Human CLDNs share approximately 95% extracellular sequence homology with their mouse counterparts, necessitating the use of divergent species for immunization Our Solution • Using discovery strategies tailored to complex membrane proteins at our partner, Integral Molecular, we isolated and characterized rare antibodies with picomolar affinity and specificity for CLDN6 • Epitope mapping at single-atom resolution identified steric hindrance near the γ-carbon of residue 156 as critical for discriminating CLDN6 versus CLDN9 binding1 Discovery of CTIM-76 CLDN6 Candidate Selection26 CLDN6 Monospecificity Challenge1 1 Screnci, iScience, 2022
Identification of Selective CLDN6 MAbs Discovery of CTIM-76 CLDN6 Candidate Selection27 • IM301 (CLDN6 arm of CTIM-76) exhibits high CLDN6 selectivity1 • Epitope mapping of IM301 identifies unique binding location relative to benchmark IMAB027/ASP150 (Ganymed/Astellas) IM171 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e IM302 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e Benchmark -10 -9 -8 -7 -6 0 50,000 100,000 150,000 hCLDN6 hCLDN9 hCLDN3 hCLDN4 Log [MAb], M M e a n F lu o re s c e n c e IM301 IM302Benchmark IM171 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e IM302 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e Benchmark -10 -9 -8 -7 -6 0 50,000 100,000 150,000 hCLDN6 hCLDN9 hCLDN3 hCLDN4 Log [MAb], M M e a n F lu o re s c e n c e IM301 IM302Benchmark IMAB027/ASP1650 IM171 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e IM302 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e Benchmark -10 -9 -8 -7 -6 0 50,000 100,000 150,000 hCLDN6 hCLDN9 hCLDN3 hCLDN4 Log [MAb], M M e a n F lu o re s c e n c e IM301 IM302Benchmark IM171 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e IM302 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e Benchmark -10 -9 -8 -7 -6 0 50,000 100,000 150,000 hCLDN6 hCLDN9 hCLDN3 hCLDN4 Log [MAb], M M e a n F lu o re s c e n c e IM301 IM302Benchmark IM171 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e IM302 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e Benchmark -10 -9 -8 -7 -6 0 50,000 100,000 150,000 hCLDN6 hCLDN9 hCLDN3 hCLDN4 Log [MAb], M M e a n F lu o re s c e n c e IM301 IM302Benchmark IM301 1 Screnci, iScience, 2022 IM171 -10 -9 -8 -7 -6 0 50,000 100,000 150,000 Log [MAb], M M e a n F lu o re s c e n c e IM302 -10 -9 -8 -7 -6 0 50, 00 100, 00 150, 00 Log [MAb], M M e a n F lu o re s c e n c e Benchmark -10 -9 -8 -7 -6 0 50, 10 , 150, hCLDN6 hCLDN9 hCLDN3 hCLDN4 [ ], M e a n F lu o re s c e n c e IM301 IM302Benchmark
CTIM-76 Exhibits Excellent Selectivity and Specificity Discovery of CTIM-76 CLDN6 Candidate Selection28 • IM301 Mab screened for specificity using Integral Molecular Membrane Proteome Array, consisting of ~6,000 human membrane proteins in their native state in unfixed cells • IM301 Mab was cross-reactive for internal control FCGR1A (Fc gamma) and intracellular epitope of ABCC3 • CTIM-76 CLDN6 EC50 of 3.41 nM • CTIM-76 preferentially binds to CLDN6 over CLDN3/4/9 • CLDN3/4/6/9 were transiently transfected in HEK-293F cells (4:1 Target:GFP) CLDN6 Selectivity CLDN6 Specificity -11 -10 -9 -8 -7 -6 -5 0 50,000 100,000 150,000 200,000 Log [Bispecific] (M) C e ll B in d in g ( M F I) Human CLDN6 Human CLDN4 Human CLDN3 Human CLDN9 Negative
Specific Lysis T-cell mediated cell killing is dependent on CLDN6 expression Discovery of CTIM-76 CLDN6 Candidate Selection29 K562-CLDN6 OV90 HEK CLDN6 Expression High Medium Low CTIM-76 (EC50) 0.0004 nM 0.049 nM 2.79 nM OV90 Cell LineK562-CLDN6 Cell Line HEK Cell Line -4 -3 -2 -1 0 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y CTIM-76 Negative Ctrl -4 -2 0 2 4 -50 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y -4 -2 0 2 4 -50 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y CTIM-76 Negative Ctrl CTIM-76 Negative Ctrl
CTIM-76 Preferentially Targets CLDN6 Over Other Claudin Family Proteins Discovery of CTIM-76 CLDN6 Candidate Selection30 • There is high sequence homology between CLDN6 and CLDN9 in the extracellular loops • CTIM-76 preferentially targets CLDN6, with minimal activity against CLDN9-expressing cells • No binding is observed to other CLDN family proteins that have <85% homology in the extracellular loops Study Design: K562 cells stably over-expressing CLDN3, CLDN4, CLDN6, or CLDN9 were co-cultured with human T-cells at an E:T ratio of 10:1 for 48 hours. Cytotoxicity was determined by luminescence imaging. CLDN6:CLDN3 CLDN6:CLDN4 -4 -3 -2 -1 0 -50 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y Negative Control CLDN6 CLDN3 -4 -3 -2 -1 0 -50 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y Negative Control CLDN6 CLDN4 Activity Gap ~836x Activity Gap ~504x CLDN6:CLDN9 -4 -3 -2 -1 0 -50 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y Negative Control CLDN6 CLDN9 Activity Gap ~1192x
Discovery of CTIM-76 CLDN6 Candidate Selection31 CTIM-76 has the Potential for a Wide Therapeutic Window • Cytokine production evaluated in exogenous (CLDN6-K562) cell line model • Cytokine production happens well above the concentration of maximal killing (EC50 = 0.0004 nM) in CLDN6-K562 cells at 48 hours • Data supports potential to dose at levels that promote cancer cell killing but have manageable levels of free cytokine production Study Design: K562 cells stably over-expressing CLDN6 and luciferase were co-cultured with human T cells at an E:T ratio of 10:1 for 48 hours. Cytotoxicity was determined by luminescence imaging. Comparison of T cell-dependent cellular cytotoxicity (TDCC) to cytokine production in CLDN6-K562 cell line CTIM-76 Cytokine Control % Lysis CTIM-76 % Lysis TDCC vs IL2 -4 -3 -2 -1 0 -50000 0 50000 100000 150000 0 20 40 60 80 100 Log [bsAb] (nM) p g /m L % S p e c ific C y to to x ic ity EC50 TDCC vs IFNg EC50 -4 -3 -2 -1 0 -50000 0 50000 100000 150000 0 20 40 60 80 100 Log [bsAb] (nM) p g /m L % S p e c ific C y to to x ic ity TDCC vs TNFα EC50 -4 -3 -2 -1 0 -500 0 500 1000 0 20 40 60 80 100 Log [bsAb] (nM) p g /m L % S p e c ific C y to to x ic ity TDCC vs IL10 EC50 -4 -3 -2 -1 0 -50 0 50 100 150 0 20 40 60 80 100 Log [bsAb] (nM) p g /m L % S p e c ific C y to to x ic ity CTIM-76 Cytokine Control % Lysis CTIM-76 % Lysis CTIM-76 Cytokine Control % Lysis CTIM-76 % Lysis CTIM-76 Cytokine Control % Lysis CTIM-76 % Lysis
Discovery of CTIM-76 CLDN6 Candidate Selection32 CTIM-76 Exhibits Ideal Immunomodulatory Properties • Exogenous (CLDN6-K562) results replicated in endogenous (OV90) cell line model • Cytokine production happens well above the concentration of maximal killing (EC50 = 0.049 nM) in OV90 cells at 48 hours Study Design:OV90 cells stably expressing luciferase were co-cultured with human T cells at an E:T ratio of 10:1 for 48 hours. Cytotoxicity was determined by luminescence imaging. Comparison of T cell-dependent cellular cytotoxicity (TDCC) to cytokine production in OV90 cell line
Role of Bispecific Format in Activity CTIM-76 format demonstrates superior potency compared to a traditional BiTE molecule Discovery of CTIM-76 CLDN6 Candidate Selection33 -4 -3 -2 -1 0 -50 0 50 100 Log [bsAb] (nM) % S p e c if ic C y to to x ic it y Negative Control IMC-2-7 CTIM-76 IMC-2-7 Tandem scFvs CTIM-76 scFv-Fab IgG Study Design: K562 cells stably expressing CLDN6 and luciferase were co-cultured with human T-cells at an E:T ratio of 10:1 for 48 hours. Cytotoxicity was determined by luminescence imaging. Activity Gap ~28x CTIM-76 vs BiTE
Concluding Remarks Martin Lehr – Chief Executive Officer
CLDN6 is an Exciting Cancer Target Within the T-cell Directed Therapy Landscape1 Concluding Remarks CLDN6 Candidate Selection35 Large Addressable Patient Population Small Addressable Patient Population Validated Target Emerging Target PRAME MAGE-A4 CLDN6 CLDN18.2 NY-ESO-1 MSLN gp100 CD19 COL6A3 AFP ENPP3 B7-H3 CD20 FLT3 BCMA GPRC5D DLL3 PSMA MUC17 1 Analysis based upon publicly available information and represents a non-head-to-head summary comparison
Competitive Landscape1 Concluding Remarks CLDN6 Candidate Selection36 Candidate IND Phase 1 ADC Bispecific Antibody Cell Therapy CAR-NK CAR-NK + IL7 secreting vector BNT211 CAR-T + CARVac TJ-46CB 2+2 bsAb CLDN6x4IBB UCLA-23-ADC CLDN6 + MMAE AMG794 BiTE CLDN6xCD3 BNT142 mRNA encoded BsAb CLDN6xCD3 Undisclosed 2+1 bsAb CLDN6xCD3 CTIM-76 bsAb CLDN6xCD3 DS-9606a CLDN6 + DXd NBL028 Fc Engineered CLDN6x4IBB GB-7008-01 CLDN6/CLDN9 + MMAE 1 Analysis based upon publicly available information
Clinical Experience for CLDN6 Therapies is Nascent Company Program Description / Details3 Active Programs BioNTech BNT211: CLDN6CAR-T + CARVac (Phase 1) Initial data for BNT211 was presented April 2022 (AACR), with an update in Sept 2022 (ESMO). Received PRIME Designation for testicular cancer June 2022 BNT142: CLDN6 mRNA encoded bsAb (Phase 1) Initiated Phase 1 development for BNT142 in mid-2022 Amgen AMG794: CLDN6 BiTE (Phase 1) AMG794 candidate was presented April 2022 (AACR), trial is not yet recruiting Guangzhou Medical University Undisclosed: CAR-NK + multiple gene edits (Phase 1) Engineered to express IL7/CCL19 and/or SCFVs against PD1/CTLA4/Lag3, initiated Phase 1 development in mid-2022 Daiichi DS-9606a: CLDN6 + DXd (Phase 1) Initiated Phase 1 development for DS-9606a in mid-2022 I-Mab TJ-46CB: CLDN6 bsAb CLDN6x4IBB (Preclinical) Initial data was presented April 2021 (AACR), IND filing is expected in 2H 2023 Xencor Undisclosed: CLDN6 bsAb CLDN6xCD3 (Preclinical) Initial data was presented April 2021 (AACR), no timeline to IND provided Notable Deprioritized Programs Astellas/Ganymed IMAB027/ASP1650: CLDN6 mAb (Phase 2) Lack of single agent activity in Phase 2 trial relapse/refractory testicular germ cell tumors1 Abbvie/Stemcentryx SC004: CLDN6/9 ADC (Phase 1) Dose-limiting toxicity observed in Phase 1 in patients with ovarian cancer2 Concluding Remarks CLDN6 Candidate Selection37 1 Adra, Invest New Drugs, 2022 2 Hamilton, Cancer Res, 2020 3 Analysis based on publicly available information compiled as of November 28, 2022
Select Early-stage Bispecific Antibody Transactions in 20221 Concluding Remarks CLDN6 Candidate Selection38 Licensee Licensor Target Asset Stage Geography Upfront ($M) Milestones ($M) TeneoTwo AstraZeneca CD19 TNB-486 Phase 1 WW $100 $1,165 Macrogenics Gilead CD123 MGD024 IND WW $60 $1,700 LAVA Seagen EGFR LAVA-1223 Preclinical WW $50 $650 Kelun Merck Claudin 18.2 SKB315 Preclinical WW (ex-China) $35 $910 CSPC Elevation Claudin 18.2 STSA1801 Preclinical WW (ex-China) $27 $148 LaNova Turning Point / BMS Claudin 18.2 LM-302 IND WW (ex-China, Korea) $25 $575 Harbour AstraZeneca Claudin 18.2 HBM7022 Preclinical WW $25 $350 1 Representative transactions based on publicly available information and represents a non-head-to-head summary comparison
Next Steps and Summary Concluding Remarks CLDN6 Candidate Selection39 Encouraging efficacy signals • CLDN6-selective activity across binding and cytotoxicity Well tolerated • Preferential cytotoxicity over activation of free circulating cytokines • PK consistent with IgG backbone • No significant safety findings to date On track for IND submission in Q1 2024 • Lonza selected as GMP manufacturing partner
MARTIN LEHR Chief Executive Officer Q&A Session ERIC BUTZ, PhD Scientific Lead JOSEPH RUCKER, PhD Research Lead JENNIFER MINAI Chief Financial Officer
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